Tipping the balance: intricate roles of the complement system in disease and therapy

Abstract

The ability of the complement system to rapidly and broadly react to microbial intruders, apoptotic cells and other threats by inducing forceful elimination responses is indispensable for its role as host defense and surveillance system. However, the danger sensing versatility of complement may come at a steep price for patients suffering from various immune, inflammatory, age-related, or biomaterial-induced conditions. Misguided recognition of cell debris or transplants, excessive activation by microbial or damaged host cells, autoimmune events, and dysregulation of the complement response may all induce effector functions that damage rather than protect host tissue. Although complement has long been associated with disease, the prevalence, impact and complexity of complement's involvement in pathological processes is only now becoming fully recognized. While complement rarely constitutes the sole driver of disease, it acts as initiator, contributor, and/or exacerbator in numerous disorders. Identifying the factors that tip complement's balance from protective to damaging effects in a particular disease continues to prove challenging. Fortunately, however, molecular insight into complement functions, improved disease models, and growing clinical experience has led to a greatly improved understanding of complement's pathological side. The identification of novel complement-mediated indications and the clinical availability of the first therapeutic complement inhibitors has also sparked a renewed interest in developing complement-targeted drugs, which meanwhile led to new approvals and promising candidates in late-stage evaluation. More than a century after its description, complement now has truly reached the clinic and the recent developments hold great promise for diagnosis and therapy alike.

Keywords: Autoimmune disease; Complement; Complement therapeutics; Hemolysis; Inflammation.

Fig. 1

Schematic overview of the complement system. The complement cascade is initiated either via the fluid-phase formation of C3(H₂O) (alternative pathway; AP) or through pattern recognition on a surface by either lectins (mannan-binding lectin; MBL, ficolins; Fcn, or collectins; CL) complexed with MASP-1 and MASP-2 (lectin pathway) or C1q complexed with C1r and C1s (classical pathway). All pathways lead to the formation of C3 convertases (C3bBb or C4b2b), which further cleave the central protein of the cascade, complement C3, into the small anaphylatoxin C3a and the larger fragment C3b. Deposition of the opsonins C4b and C3b on targeted surfaces mediates signaling through complement receptors (CR) on immune cells, induces cell activation, and facilitates phagocytosis. In parallel, C3b deposition perpetuates the cascade by forming new C3 convertases via the AP, also referred to as the amplification loop. This positive feedback loop leads to more C3b deposition that, at a sufficient density, turns C3 convertases into C5 convertases, which cleave C5 into the small anaphylatoxin C5a and the larger C5b. C5b is a nucleus for the formation of the membrane attack complex (MAC, C5b-9), via subsequent binding of C6, C7, C8, and multiple C9, forming the lytic pore. C5a and C3a induce chemotaxis and inflammatory responses via their C5a and C3a receptors (C5aR1/C5aR2 and C3aR, respectively) but are quickly degraded in plasma to their less potent forms C5a-desArg and C3a-desArg, respectively. The cascade is regulated at various steps, here indicated in red. FH and FHL-1 control the alternative pathway, whereas MAPs and C1-INH control the initiation of the lectin or classical pathway, with the latter acting on both. On the host surface, several additional regulators act on the formation of C3 convertases, as well as acting as co-factors for the degradation of the opsonins by FI. The extent of cleavage by FI depends on its co-factor: (1) C3(H₂O) to iC3(H₂O) requires FH/FHL-1; (2) C3b to iC3b occurs in the presence of FH, FHL-1, CD46 (or membrane cofactor protein; MCP), CR1 and the more recently described Sez6 protein family and CSMD1; (3) iC3b is further degraded to C3dg in the presence of CD46, CR1, Sez6, and CSMD1; (4) C4b is degraded to iC4b; and (5) subsequently C4d in the presence of C4BP, CR1, CD46, and CSMD1. While the remaining fragments can no longer perpetuate the complement cascade, they are still ligands for CRs. The decay of the convertases is accelerated by CD55 (or decay accelerating factor; DAF), CR1, CSMD1, FH/FHL-1, and Sez6 (C3b-based convertases only), and C4BP (C4b-based convertases only). The formation of the lytic ring by C9 is inhibited by CD59. New regulatory steps continue to be uncovered, including FHRs that might regulate FH/FHL-1, thereby preventing complement inhibition, whereas FHR-5 might add a new class of regulators to the system, acting specifically on C5 convertases. The extent of properdin stabilizing the C3b-based convertases remains topic of debate, possibly acting as a pattern recognition molecule for the alternative pathway or even comprising its own pathway in parallel to the three traditional ones. The role of MASP-3, a splice variant of the LP zymogen MASP-1, has only recently been appreciated, essentially enabling the maturation of pro-FD into FD

Fig. 2

Principal mechanisms of complement involvement in disease. A The reaction of complement toward different surfaces is largely driven by the sum of stimulatory (orange circles) and regulatory entities (green circles). Under physiological conditions, this enables immune surveillance by forcefully removing microbial intruders and silently clearing endogenous threats while sparing healthy host cells. However, hyperactivation of the system by massive influx of bacteria (sepsis) may lead to strong bystander attack of host cells that overpower the regulatory capacity, while the inflicted cell damage may exacerbate the response. Biomaterials (e.g., liposomes), auto-antibodies (e.g., in AIHA), cell debris (e.g., atherosclerotic plaque), or hypoxia-induced damage patterns may trigger a misguided complement response that induces cell damage (e.g., reperfusion injury), inflammation, and/or adverse crosstalk reactions. Finally, insufficient regulation on host cells may increase their vulnerability to complement attack (e.g., by bystander activation). B Most complement-related conditions are driven by excessive activation and/or insufficient regulation of the complement response. However, exploitation of complement regulation is also observed as part of the immune invasion strategy of many pathogens and cancer cells

Fig. 3

Complement-targeted therapeutics in the clinic or in late-stage development. Following eculizumab, the first complement-targeting therapeutic approved for a complement-driven disease (PNH), similar and novel therapeutic strategies are now at the final stage of development and on the verge of entering the clinic. Various inhibitors and biologicals act on C5, expanding on the success of eculizumab while fine-tuning the therapeutic strategy by specifically targeting C5a or its receptor (e.g., interfering with anaphylatoxin responses, while leaving MAC formation intact). Of special interest will be pegcetacoplan, as the first approved complement therapeutic that is acting more upstream within the cascade, closely followed by activation pathway-specific inhibitors. Of special note are preparations of C1 esterase inhibitor, a serine protease inhibitor which has been long used in the treatment of hereditary angioedema, unrelated to its effect on the lectin and classical activation pathways. With the rise of complement-targeting therapeutics, C1 esterase inhibitor have gained renewed interest as potential complement therapeutic that is easily accessible for the clinic. Furthermore, additional biologicals acting on the activation pathways are being explored, with narsoplimab (anti-MASP-2) and sutimlimab (anti-C1s) being the most advanced in development